This invention relates generally to amino-thio-acrylonitriles as MEK inhibitors, pharmaceutical compositions containing the same, and methods of using the same as for treatment and prevention of inflammatory disorders, cancer or other proliferative diseases or as a radiosensitizing agents against cancer or other proliferative disorders.
The mitogen activated protein kinase (MAPK) signaling pathways are involved in cellular events such as growth, differentiation and stress responses (J. Biol. Chem. (1993) 268, 14553-14556). Four parallel pathways have been identified to date ERK1/ERK2, JNK, p38 and ERK5. These pathways are linear kinase cascades in that MAPKKK phosphorylates and activates MAPKK that phosphorylates and activates MAPK. To date, there are 7 MAPKK homologs (MEK1, MEK2, MKK3, MKK4/SEK, MEK5, MKK6, and MKK7) and 4 MAPK families (ERK1/2, JNK, p38, and ERK5). The MAPKK family members are unique in that they are dual-specific kinases, phosphorylating MAPKs on threonine and tyrosine. Activation of these pathways regulates the activity of a number of substrates through phosphorylation. These substrates include transcription factors such as TCF, c-myc, ATF2 and the AP-1 components, fos and Jun; the cell surface components EGF-R; cytosolic components including PHAS-I, p90rsk, cPLA2 and c-Raf-1; and the cytoskeleton components such as tau and MAP2.
The prototypical mitogen activated protein kinase cascade is reflected by the ERK pathway (Biochem J. (1995) 309, 361-375). The ERK pathway is activated primarily in response to ligation of receptor tyrosine kinases (RTKs) (FEBS Lett. (1993) 334, 189-192). Signal propagation from the RTKs occurs down the Ras pathway through sequential phosphorylation of Raf, MEK and ERK. This pathway has not been typically viewed of as an important contributor to the inflammatory response, but rather involved in growth and differentiation processes. This view stems from the profile of typical activators of this pathway, which include growth factors (PDGF, NGF, EGF), mitogens (phorbol esters), and polypeptide hormones (insulin, IGF-1). Evidence for ERK pathway involvement in inflammatory and immune responses has, however, gained some support in recent years (Proc. Natl. Acad. Sci. USA. (1995) 92, 1614-1618; J. Immunol. (1995) 155, 1525-1533; and J. Biol. Chem. (1995) 270, 27391-27394). Cytokines such as TNFa and IL-1b, the bacterial cell wall mitogen, LPS, and chemotactic factors such as fMLP, C5a, and IL-8 all activate the ERK pathway. In addition, the ERK pathway is activated as a result of T cell receptor ligation with antigen or agents such as PMA/ionomycin or anti-CD3 antibody, which mimic TCR ligation in T cells (Proc. Natl. Acad. Sci. USA (1995) 92, 7686-7689). These findings indicate that inhibitors of the ERK pathway should function as anti-inflammatory and immune suppressive agents.
Small molecule inhibitors of the Raf/MEK/ERK pathway have been identified. A series of benzoquinones has been disclosed by Parke-Davis, which is exemplified by PD 098059 that inhibits MEK activity (J. Biol. Chem. (1995) 46, 27498-27494). Recently, we identified a MEK inhibitor, U0126 (J. Biol. Chem. (1998) 29, 18623-18632). Comparative kinetic analysis showed that U0126 and PD 098059 were non-competitive inhibitors of activated MEK (J. Biol. Chem. (1998) 29, 18623-18632). These MEK inhibitors have been used to investigate the role of the ERK activation cascade in a wide variety of systems including inflammation, immune suppression and cancer. For example, PD 098059 blocks thymidine incorporation into DNA in PDGF-stimulated Swiss 3T3 cells (J. Biol. Chem. (1995) 46, 27498-27494). PD 098059 also prevents PDGF-BB-dependent SMC (Smooth Muscle Cell) chemotaxis at concentrations which inhibit ERK activation (Hypertension (1997) 29, 334-339). Similarly, U0126 prevents PDGF-dependent growth of serum starved SMC. We have also shown that U0126 blocks keratinocyte proliferation in response to a pituitary growth factor extract, which consists primarily of FGF. These data coupled with those obtained with PD 098059 above indicate that MEK activity is essential for growth factor-stimulated proliferation.
The role of the MEK/ERK pathway in inflammation and immune suppression has been examined in a number of systems, including models of T cell activation. The T cell antigen receptor (TCR) is a non-RTK receptor whose intracellular signaling pathways have been elucidated (Proc. Natl. Acad. Sci. USA (1995) 92, 7686-7689). DeSilva et al. have generated a great deal of information with U0126 in T cell systems (J. Immunol. (1998) 160, 4175-4181). Their data showed that U0126 prevents ERK activation in T cells in response to PMA/ionomycin, Con A stimulation, and antigen in the presence of costimulation. In addition, T cell activation and proliferation in response TCR engagement is blocked by U0126 as is IL-2 synthesis. These results indicate that MEK inhibition does not result in a general antiproliferative effect in this IL-2-driven system, but selectively blocks components of the signaling cascades initiated by T cell receptor engagement.
PD 098059 has also been shown to inhibit T cell proliferation in response to anti-CD3 antibody, which is reversed by IL-2 (J. Immunol. (1998) 160, 2579-2589.). PD 098059 also blocked IL-2 production by T cells stimulated with anti-CD3 antibody in combination with either anti-CD28 or PMA. In addition, the MEK inhibitor blocked TNFa, IL-3 GM-CSF, IFN-g, IL-6 and IL-10 production. In contrast, PD 098059 enhanced production of IL-4, IL-5 and IL-13 in similarly stimulated T cell cultures. These differential T cells effects with MEK inhibition suggest that therapeutic manipulations may be possible.
Neutrophils show ERK activation in response to the agonists N-formyl peptide (fMLP), IL-8, C5a and LTB4, which is blocked by PD 098059 (Biochem. Biophy. Res. Commun. (1997) 232, 474-477). Additionally, PD 098059 blocks neutrophil chemotaxis in response to all agents, but does not alter superoxide anion production. However, fMLP-stimulated superoxide generation was inhibited by PD098059 in HL-60 cells (J. Immunol. (1997) 159, 5070-5078), suggesting that this effect may be cell-type specific. U0126 blocks ERK activation in fMLP- and LTB4-stimulated neutrophils, but does not impair NADPH-oxidase activity or bacterial cell killing. U0126 at 10 mM blunts up regulation of b2 integrin on the cell surface by 50% and blocks chemotaxis through a fibrin gel  greater than 80% in response to IL-8 and LTB4. Thus, neutrophil mobility is affected by MEK inhibition although the acute functional responses of the cell remain intact.
Eicosanoids are key mediators of the inflammatory response. The proximal event leading to prostaglandin and leukotriene biosynthesis is arachidonic acid release from membrane stores, which is mediated largely through the action of cytosolic phospholipase A2 (cPLA2). Activation of cPLA2 requires Ca2+ along with phosphorylation on a consensus MAP kinase site, Ser505, which increases catalytic efficiency of the enzyme (J. Biol. Chem. (1997) 272, 16709-16712). In neutrophils, mast cells, or endothelial cells, PD 098059 blocks arachidonic acid release in response to opsonized zymosan, aggregation of the high affinity IgG receptor, or thrombin, respectively. Such data support a role for ERK as the mediator of cPLA2 activation through phosphorylation (FEBS Lett. (1996) 388, 180-184. Biochem J. (1997) 326, 867-876 and J. Biol. Chem. (1997) 272, 13397-13402). Similarly, U0126 is able to block arachidonic acid release along with prostaglandin and leukotriene synthesis in keratinocytes stimulated with a variety of agents. Thus, the effector target, cPLA2, is sensitive to MEK inhibition in a variety of cell types.
MEK inhibitors also seem to affect eicosanoid production through means other than inhibition of arachidonic acid release. PD 098059 partially blocked LPS-induced Cox-2 expression in RAW 264.7 cells, indicating ERK activation alone may not be sufficient to induce expression of this key enzyme mediating inflammatory prostanoid production (Biochem J. (1998) 330, 1107-1114). Similarly, U0126 inhibits Cox-2 induction in TPA-stimulated fibroblasts, although it does not impede serum induction of the Cox-2 transcript. PD 098059 also inhibits Cox-2 induction in lysophosphatidic acid (LPA)-stimulated rat mesangial cells, which further supports a role for ERK activation in production of prostaglandins (Biochem J. (1998) 330, 1107-1114). Finally, 5-lipoxygenase translocation from the cytosol to the nuclear membrane along with its activation as measured by 5-HETE production can be inhibited by PD 098059 in HL-60 cells (Arch. Biochem. Biophys; (1996) 331, 141-144).
Inflammatory cytokines such as TNFa and IL-1b are critical components of the inflammatory response. Cytokine production in response to cell activation by various stimuli as well as their activation of downstream signaling cascades represent novel targets for therapeutics. Although the primary effect of IL-1b and TNF-a is to up regulate the stress pathways (Nature (1994) 372, 729-746), published reports (Proc. Natl. Acad. Sci. USA (1995) 92, 1614-1618. J. Immunol. (1995) 155, 1525-1533. J. Biol. Chem. (1995) 270, 27391-27394. Eur. J.). Cytokines such as TNFa and IL-1b, the bacterial cell wall mitogen, LPS, and chemotactic factors such as fMLP, C5a, and IL-8 all activate the ERK pathway. In addition, the ERK pathway is activated as a result of T cell receptor ligation with antigen or agents such as PMA/ionomycin or anti-CD3 antibody, which mimic TCR ligation in T cells (Proc. Natl. Acad. Sci. USA (1995) 92, 7686-7689) and clearly show that the ERK pathway is also affected. U0126 can block MMP induction by IL-1b and TNF-a in fibroblasts (J. Biol. Chem. (1998) 29, 18623-18632), demonstrating that ERK activation is necessary for this proinflammatory function. Similarly, lipopolysaccharide (LPS) treatment of monocytes results in cytokine production that has been shown to be MAP kinase-dependent being blocked by PD 098059 (J. Immunnol. (1998) 160, 920-928). Indeed, we have observed similar results in freshly isolated human monocytes and THP-1 cells where LPS-induced cytokine production is inhibitable by U0126 (J. Immunol. (1998) 161:5681-5686).
The proximal involvement of RAS in the activation of the ERK pathway suggests that MEK inhibition might show efficacy in models where oncogenic RAS is a determinant in the cancer phenotype. Indeed, PD 098059 (J. Biol. Chem. (1995) 46, 27498-27494) as well as U0126 are able to impede the growth of RAS-transformed cells in soft agar even though these compounds show minimal effects on cell growth under normal culture conditions. We have further examined the effects of U0126 on the growth of human tumor cell lines in soft agar. We have shown that U0126 can prevent cell growth in some cells, but not all, suggesting that a MEK inhibitor may be effective in only certain kinds of cancer. In addition, PD 098059 has been shown to reduce urokinase secretion controlled by growth factors such as EGF, TGFa and FGF in an autocrine fashion in the squamous cell carcinoma cell lines UM-SCC-1 and MDA-TV-138 (Cancer Res. (1996) 56, 5369-5374). In vitro invasiveness of UM-SCC-1 cells through an extracellular matrix-coated porous filter was blocked by PD 098059 although cellular proliferation rate was not affected. These results indicate that control of the tumor invasive phenotype by MEK inhibition may also be a possibility. The observed effects with PD 098059 and U0126 suggest that MEK inhibition may have potential for efficacy in a number of disease states. Our own data argue strongly for the use of MEK inhibitors in T-cell mediated diseases where immune suppression would be of value. Prevention of organ transplant rejection, graft versus host disease, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis are potential disease targets. Effects in acute and chronic inflammatory conditions are supported by the results in neutrophils and macrophage systems where MEK inhibition blocks cell migration and liberation of proinflammatory cytokines. A use in conditions where neutrophil influx drives tissue destruction such as reperfusion injury in myocardial infarction and stroke as well as inflammatory arthritis may be warranted. Blunting of SMC migration and inhibition of DNA replication would suggest atherosclerosis along with restenosis following angioplasty as disease indications for MEK inhibitors. Skin disease such as psoriasis provides another potential area where MEK inhibitors may prove useful since MEK inhibition prevents skin edema in mice in response to TPA. MEK inhibition also blocks keratinocyte responses to growth factor cocktails, which are known mediators in the psoriatic process.
Finally, the use of a MEK inhibitor in cancer can not be overlooked. Ionizing radiation initiates a process of apoptosis or cell death that is useful in the treatment solid tumors. This process involves a balance between pro-apoptotic and anti-apoptotic signal (Science 239, 645-647), which include activation of MAP kinase cascades. Activation of the SAPK pathway delivers a pro-apoptotic signal (Radiotherapy and Oncology (1998) 47, 225-232.), whereas activation of the MAPK pathway is anti-apoptotic (Nature (1996) 328, 813-816.). Interference with the anti-apoptotic MAPK pathway by dominant negative MEK2 or through direct inhibition of MEK with synthetic inhibitors sensitizes cells to radiation-induced cell death (J. Biol. Chem. (1999) 274, 2732-2742; and Oncogene (1998) 16, 2787-2796).
WO98/37881 describe MEK inhibitors useful for treating or preventing septic shock. The inhibitors include 2-(2-amino-3-methoxyphenyl)-4-oxo-4H-[1]benzopyran and a compound of the formula: 
The above diphenyl amines are not considered to be part of the presently claimed invention.
Therefore, efficacious and specific MEK inhibitors are needed as potentially valuable therapeutic agents for the treatment of inflammatory disorders, cancer or other proliferative diseases or as a radiosensitizing agents against cancer or other proliferative disorders. It is thus desirable to discover new MEK inhibitors.
Accordingly, one object of the present invention is to provide novel amino-thio-acrylonitriles which are useful as MEK inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating a disorder involving MEK, comprising: administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a novel method of using the compounds of the present invention as a radiosensitizing agent for the treatment of cancers or proliferative diseases, comprising: administering to a host in need of such treatment a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable prodrug or salt form thereof.
It is another object of the present invention to provide a novel method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, multiple sclerosis, or psoriasis in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide a novel method of treating a condition or disease wherein the disease or condition is referred to as fever, cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease or HIV infection in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide novel amino-thio-acrylonitriles or salts or prodrugs thereof for use in therapy.
It is another object of the present invention to provide the use of novel amino-thio-acrylonitriles or salts or prodrugs thereof for the manufacture of a medicament for the treatment of an inflammatory disease.
It is another object of the present invention to provide the use of novel amino-thio-acrylonitriles or salts or prodrugs thereof for the manufacture of a medicament for the treatment of cancer.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula Ia or Ib: 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein R1 and R2 are defined below, are effective MEK inhibitors.
Thus, in a first embodiment, the present invention provides a novel compound of formula Ia or Ib: 
or stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
R1 is phenyl, naphthyl, 2,3-dihydroindol-5-yl or a 5-6 membered heteroaryl ring with 1-4 heteroatoms selected from N, NH, O, and S, and R1 is substituted with 0-2 Ra;
Ra is selected from H, Cl, F, Br, I, C1-4 alkyl, C1-4 alkoxy, OH, CH2OH, NH2, (C1-3 alkyl)NH, (C1-3 alkyl)2N, (H2NCH2C(O))NH, (H2NCH(CH3)C(O))NH, (CH3NHCH2C(O))NH, ((CH3)2NCH2C(O))NH, CF3, OCF3, xe2x80x94CN, NO2, C(O)NH2, and CH3C(O)NH;
Y is selected from phenyl substituted with 0-5 Rb, naphthyl substituted with 0-5 Rb, and CHR3;
Rb is selected from H, Cl, F, Br, I, C1-4 alkyl, OH, C1-4 alkoxy, CH2OH, CH(OH)CH3, CF3, OCF3, xe2x80x94CN, NO2, NH2, (C1-3 alkyl)NH, (C1-3 alkyl)2N, and C(O)Oxe2x80x94C1-4 alkoxy;
R2 is selected from H, R2a, C(O)R2a, CH(OH)R2a, CH2R2a, OR2a, SR2a, and NHR2a;
R2a is selected from phenyl, naphthyl, and a 5-6 membered heteroaryl ring with 1-4 heteroatoms selected from N, NH, O, and S, and R2a is substituted with 0-5 Rb;
R3 is phenyl substituted with 0-2 Rc or naphthyl substituted with 0-2 Rc; and,
Rc is selected from H, Cl, F, Br, I, C1-4 alkyl, OH, C1-4 alkoxy, CH2OH, CH(OH)CH3, CF3, OCF3, xe2x80x94CN, NO2, NH2, (C1-3 alkyl)NH, (C1-3 alkyl)2N, and C(O)Oxe2x80x94C1-4 alkoxy.
In a preferred embodiment, the present invention provides a novel compound, wherein:
R1 is phenyl or a 5-6 membered heteroaryl ring with 1-2 heteroatoms selected from N, NH, O, and S, and R1 is substituted with 0-2 Ra;
Ra is selected from H, Cl, F, C1-4 alkyl, C1-4 alkoxy, OH, CH2OH, NH2, (C1-3 alkyl)NH, (C1-3 alkyl)2N, (H2NCH2C(O))NH, (H2NCH(CH3)C(O))NH, (CH3NHCH2C(O))NH, ((CH3)2NCH2C(O))NH, and CH3C(O)NH;
Y is selected from phenyl substituted with 0-5 Rb, naphthyl substituted with 0-5 Rb, and CHR3;
Rb is selected from H, Cl, F, Br, C1-4 alkyl, OH, C1-4 alkoxy, CH2OH, CH(OH)CH3, CF3, xe2x80x94CN, NO2, NH2, and (C1-3 alkyl)NH, (C1-3 alkyl)2N;
R2 is selected from H, R2a, C(O)R2a, CH(OH)R2a, CH2R2a, and OR2a;
R2a is selected from phenyl, naphthyl, and a 5-6 membered heteroaryl ring with 1-4 heteroatoms selected from N, NH, O, and S, and R2a is substituted with 0-5 Rb;
R3 is phenyl substituted with 0-2 Rc or naphthyl substituted with 0-2 Rc; and,
Rc is selected from H, Cl, F, Br, I, C1-4 alkyl, OH, C1-4 alkoxy, CH2OH, CH(OH)CH3, CF3, xe2x80x94CN, NO2, NH2, (C1-3 alkyl)NH, and (C1-3 alkyl)2N.
In a more preferred embodiment, the present invention provides a novel compound, wherein:
R1 is phenyl or a 5-6 membered heteroaryl ring with 1-2 heteroatoms selected from N, NH, O, and S, and R1 is substituted with 0-2 Ra;
Ra is selected from H, OH, and NH2;
Y is selected from phenyl substituted with 0-2 Rb, naphthyl substituted with 0-2 Rb, and CHR3;
Rb is selected from H, Cl, F, Br, C1-4 alkyl, OH, C1-4 alkoxy, CH2OH, CH(OH)CH3, CF3, xe2x80x94CN, NO2, NH2, and (C1-3 alkyl)NH, (C1-3 alkyl)2N;
R2 is selected from H, R2a, C(O)R2a, CH(OH)R2a, CH2R2a, and OR2a;
R2a is selected from phenyl, naphthyl, and a 5-6 membered heteroaryl ring with 1-4 heteroatoms selected from N, NH, O, and S, and R2a is substituted with 0-5 Rb;
R3 is phenyl substituted with 0-2 Rc or naphthyl substituted with 0-2 Rc; and,
Rc is selected from H, Cl, F, Br, I, C1-4 alkyl, OH, C1-4 alkoxy, CH2OH, CH(OH)CH3, CF3, xe2x80x94CN, NO2, NH2, (C1-3 alkyl)NH, and (C1-3 alkyl)2N.
In an even more preferred embodiment, the present invention provides a novel compound selected from:
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-4-chloro-2-methyl-xcex2-phenylbenzenepropanenitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dinitrophenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(4-carbomethoxyphenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(4-nitrophenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(3-nitrophenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2-trifluoromethylphenyl)hydroxymethyl]benzeneacetonitrile
E- and Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(4-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(3-cyanophenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino(phenylthio)methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino(phenylthio)methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dimethylphenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2-thienyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-4-chloro-xcex2-phenylbenzenepropanenitrile;
E- and Z-xcex1-[amino[(2-thienyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2,4-diaminophenyl)thio]methylene]-1-naphthyleneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-xcex2-(4-pyridyl)benzenepropanenitrile;
E- and Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-3-(benzyl)benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-naphthyl)thio]methylene]-1-naphthyleneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-(benzoyl)benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-xcex2-(1-methyl-2-pyrrolyl)benzenepropanenitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-phenoxybenzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2-furanyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-thienyl)thio]methylene]-3-[(2,3,4,5,6-pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(3-methyl-2-pyridyl)hydroxymethyl]benzeneacetonitrile;
E- and Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;
E- and Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-4-(1,1-dimethylethyl)benzeneacetonitrile;
E- and Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-(trifluoromethyl)benzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile;
E- and Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-4-methylbenzeneacetonitrile;
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;
E- and Z-xcex1-[amino[(2-fluorophenyl)thio]methylene]-1-naphthyleneacetonitrile; and,
E- and Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-phenyl benzeneacetonitrile;
or a pharmaceutically acceptable salt form thereof.
In a further preferred embodiment, the present invention provides a novel compound selected from:
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-4-chloro-2-methyl-xcex2-phenylbenzenepropanenitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dinitrophenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(4-carbomethoxyphenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(4-nitrophenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(3-nitrophenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2-trifluoromethylphenyl)hydroxymethyl]benzeneacetonitrile
E-xcex1-[amino[(4-aminophenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(4-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(3-cyanophenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(4-aminophenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino(phenylthio)methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino(phenylthio)methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(4-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dimethylphenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2-thienyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-4-chloro-xcex2-phenylbenzenepropanenitrile;
E-xcex1-[amino[(2-thienyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2,4-diaminophenyl)thio]methylene]-1-naphthyleneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-xcex2-(4-pyridyl)benzenepropanenitrile;
E-xcex1-[amino[(4-aminophenyl)thio]methylene]-3-(benzyl)benzeneacetonitrile;
E-xcex1-[amino[(2-naphthyl)thio]methylene]-1-naphthyleneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-(benzoyl)benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-xcex2-(1-methyl-2-pyrrolyl)benzenepropanenitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-phenoxybenzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2-furanyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-thienyl)thio]methylene]-3-[(2,3,4,5,6-pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(3-methyl-2-pyridyl)hydroxymethyl]benzeneacetonitrile;
E-xcex1-[amino[(4-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;
E-xcex1-[amino[(4-aminophenyl)thio]methylene]-4-(1,1-dimethylethyl)benzeneacetonitrile;
E-xcex1-[amino[(4-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-(trifluoromethyl)benzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile;
E-xcex1-[amino[(4-aminophenyl)thio]methylene]-4-methylbenzeneacetonitrile;
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;
E-xcex1-[amino[(2-fluorophenyl)thio]methylene]-1-naphthyleneacetonitrile; and,
E-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-phenyl benzeneacetonitrile;
or a pharmaceutically acceptable salt form thereof.
In a further preferred embodiment, the present invention provides a novel compound selected from:
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-4-chloro-2-methyl-xcex2-phenylbenzenepropanenitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dinitrophenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(4-carbomethoxyphenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(4-nitrophenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(3-nitrophenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2-trifluoromethylphenyl)hydroxymethyl]benzeneacetonitrile
Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(4-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(3-cyanophenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino(phenylthio)methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino(phenylthio)methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dimethylphenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2-thienyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-4-chloro-xcex2-phenylbenzenepropanenitrile;
Z-xcex1-[amino[(2-thienyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2,4-diaminophenyl)thio]methylene]-1-naphthyleneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methyl-xcex2-(4-pyridyl)benzenepropanenitrile;
Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-3-(benzyl)benzeneacetonitrile;
Z-xcex1-[amino[(2-naphthyl)thio]methylene]-1-naphthyleneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-(benzoyl)benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-xcex2-(1-methyl-2-pyrrolyl)benzenepropanenitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-phenoxybenzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(2furanyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-thienyl)thio]methylene]-3-[(2,3,4,5,6-pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-[(3-methyl-2-pyridyl)hydroxymethyl]benzeneacetonitrile;
Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;
Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-4-(1,1-dimethylethyl)benzeneacetonitrile;
Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-(trifluoromethyl)benzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile;
Z-xcex1-[amino[(4-aminophenyl)thio]methylene]-4-methylbenzeneacetonitrile;
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;
Z-xcex1-[amino[(2-fluorophenyl)thio]methylene]-1-naphthyleneacetonitrile; and,
Z-xcex1-[amino[(2-aminophenyl)thio]methylene]-3-phenyl benzeneacetonitrile;
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula Ia or Ib or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating or preventing a disorder related to MEK, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula Ia or Ib or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides novel compounds of formula Ia or Ib or a pharmaceutically acceptable salt form thereof for use in therapy.
In another embodiment, the present invention provides novel compounds of formula Ia or Ib or a pharmaceutically acceptable salt form thereof for the manufacture of a medicament for the treatment of an inflammatory disease.
In another embodiment, the present invention provides novel compounds of formula Ia or Ib or a pharmaceutically acceptable salt form thereof for the manufacture of a medicament for the treatment of cancer.
In another embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, multiple sclerosis, or psoriasis in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as fever, cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease or HIV infection in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
xe2x80x9cSubstitutedxe2x80x9d is intended to indicate that one or more hydrogens on the atom indicated in the expression using xe2x80x9csubstitutedxe2x80x9d is replaced with a selection from the indicated group(s), provided that the indicated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O) group, then 2 hydrogens on the atom are replaced.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-4 alkyl is intended to include C1, C2, C3, and C4 alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-4 alkoxy is intended to include C1, C2, C3, and C4, alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5 or 6 membered monocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, O and S. It is to be noted that that the total number of S and O atoms in an aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 2H,6H-1,5,2-dithiazinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, pyrimidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, 2H-pyrrolyl, pyrrolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, and imidazolyl.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula Ia or Ib in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula Ia or Ib are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula Ia or Ib wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula Ia or Ib is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula Ia or Ib.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit MEK or treat the symptoms of MEK over production in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, MEK inhibition) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
The term xe2x80x9cradiosensitizexe2x80x9d, as used herein refers to a process whereby cells are made susceptible to radiation-induced cell death, or the cells that result from the process.
The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.
Compounds of the present invention (3) may be synthesized by the route described in Scheme 1. A thiol 1, such as a thiophenol, may be treated with a malononitrile such as malononitrile 2 in the presence of a base catalyst such as triethylamine, DBU, Hunig""s base, or aqueous base (for example, 10% NaOH), etc., in a nonreactive solvent such as THF, acetone, etc., to yield the vinylogous cyanamide 3. The reaction medium can be degassed to eliminate the presence of oxygen which can facilitate disulfide formation via the dimerization of thiol 1. The vinylogous cyanamide is frequently isolated as a mixture of Z- and E-isomers and the melting point varies significantly with isomer composition. A crystalline single isomer or material enriched in one isomer may sometimes be obtained by spontaneous crystallization of one isomer, recrystallization, or stirring solid in a solvent which dissolves only part of the material. Alternatively, isomers may sometimes be separated by chromatography. However, the double bond in 3 isomerizes very easily. NMR spectroscopy of a single isomer in DMSO-d6 shows that an equilibrium mixture of Z- and E-isomers is generated faster than the spectrum could be obtained (about 5 minutes). Isomerization also takes place in other solvents such as water, acetone, methanol, and chloroform, but more slowly than in DMSO. Rapid NMR in one of these solvents may be used to establish isomeric composition. For in vitro assays, the compounds may be dissolved in DMSO to ensure that an equilibrium mixture of isomers is tested. 
Many thiols (1) are commercially available. Alternatively, there are many methods for their synthesis familiar to one skilled in the art. For example, aryl or heterocyclic anions may be quenched with sulfur to yield thiols (Chem. Pharm. Bull. 1989, 37 (1), 36). Displacement of aryldiazonium salts with EtOCS2K leads to aryl thiols (Collect. Czech. Chem. Commun. 1990, 55, 1266). The Newman rearrangement of phenols via their dimethylthiocarbamates leads to thiophenols (Organic Syntheses VI, (1988) 824).
When the Y group in Scheme 1 is substituted phenyl or naphthyl, the malononitrile precursors (2) to the compounds of this invention may be prepared by one of the three routes shown in Scheme 2. In the first route, aryl iodides 4 may be treated with malononitrile in the presence of a copper catalyst to yield arylmalononitriles 2 (J. Org. Chem. 1993 (58) 7606-7). Malononitrile can also be coupled to aryl halides 4 (X=halide) using. (Ph3P)2PdCl2 or Pd(Ph3P)4 in THF (J. Chem. Soc. Chem. Comm. 1984, 932-3). The aryl iodides needed for these methods are commercially available or prepared by methods familiar to one skilled in the art. In particular, aryl iodides may be prepared by iodination with a source of electrophilic iodine, such as iodine monochloride, or by diazotization of anilines. 
Arylmalononitriles may also be prepared from aryl acetonitriles as shown the second route in Scheme 2. Aryl acetonitriles 5 may be deprotonated with a base, such as LDA, and quenched with a electrophilic source of cyanide, such as cyanogen chloride (J. Org. Chem. 1966, 21, 919) or 2-chlorobenzylthiocyanate (J. Org. Chem. 1983, 48, 2774-5) to yield malononitrile 2. Along the same lines, acetonitrile 5 can also be acylated in the presence of NaOMe with dimethyl carbonate to form the methyl cyanoacetate (not shown in Scheme 2). Conversion of the methyl ester to a nitrile group via procedures familiar to one skilled in the art leads to malononitrile 2 (J. Am. Chem. Soc. 1904, 32, 119). The aryl acetonitriles needed for these methods are commercially available or prepared by methods familiar to one skilled in the art, for example, from aryl acetamides or from toluenes. When R2 is an optionally substituted phenoxy group, the initial step in the preparation of the compounds of this invention may be an Ullmann condensation between an aryl halide and a phenol. (For useful protocols, see: U.S. Pat. No. 4,288,386; and Tetrahedron (1961), 15, 144-153.) A methyl substituent on either of these substrates may be subsequently converted to a xe2x80x94CH2CN group by free radical halogenation, with a reagent such as N-bromosuccinimide, followed by displacement with cyanide.
As shown in the third route shown in Scheme 2, arylmalononitriles 2 may also be synthesized from simpler bromo- or iodoarylmalononitriles. These bromo- or iodo-substituted arylmalononitriles may be prepared by either of the first two routes indicated in Scheme 2 for the preparation of malononitriles. Bromo- or iodo-substituted arylmalononitriles undergo halogen-metal exchange in the presence of two or more equivalents of an alkyllithium reagent, such as n-butyllithium, to form dianion intermediate 7. This process may be carried out in an ethereal solvent such as THF at a temperature of xe2x88x9278 to 0xc2x0 C. The dianion may be quenched in situ with one equivalent of an electrophile, such as an aldehyde, alkyl halide, disulfide, ester, or ketone, to yield a substituted malononitrile 2 with a new R2 group attached to the former site of the bromine or iodine atom. This is process is illustrated in more detail in Scheme 3 for the case where Y is a 1,3-disubstituted phenyl group. 3-Bromophenylmalononitrile (6) may be converted to dianion 7a 
by deprotonation and halogen-metal exchange with 2 equivalents of n-butyllithium in THF at xe2x88x9278xc2x0 C. The dianion may be treated in situ with an aldehyde to produce hydroxy-phenylmalononitriles 8. Hydroxy-phenylmalononitriles 8 may be oxidized to the corresponding keto-phenylmalononitrile 9 using MnO2 or a variety of other oxidizing agents familiar to one skilled in the art. Compounds 8 and 9 may be reduced to the corresponding CH2R2-substituted phenylmalononitriles 10 using hydrogen and a noble metal catalyst, NaBH4 and TFA (Synthesis 1978, 763-5), or other procedures familiar to one skilled in the art. Malononitriles 8, 9, and 10 may be treated with thiols 1 to yield the compounds of this invention. It must be noted that although only the meta-bromo isomer of 6 is pictured in Scheme 3, one trained in the art may apply this methodology using other aryl halides and electrophiles to prepare isomers and compounds with different Y groups. 
When Y is CHR3, malononitrile precursors useful for preparation of the compounds of this invention have structure 2a and may be prepared as shown in Scheme 4. Knoevenagel condensation (Organic Reactions 15, 204-509 (1967)) between an aldehyde 11 or a ketone 13 may be used to produce alkylidene malononitriles 12 or 14. Conjugate addition of a Grignard or organolithium reagent to 12 affords the malononitrile prescursors 2 used in Scheme 1. Alternatively, alkylidene malononitriles 14 may be reduced to malononitriles 2a with sodium borohydride, catalytic hydrogenation or other reducing agents familiar to one skilled in the art. A third alternative is to alkylate malononitrile with an alkyl halide 15 (X=halide).